PROJECT SUMMARY/ABSTRACT: Obesity-induced inflammation contributes to the development of insulin resistance and Type 2 Diabetes (T2D). The gut plays an important yet poorly understood role in the development of T2D. Mounting evidence implicates impaired intestinal immune responses and dysbiosis of the gut microbiota in driving the onset of insulin resistance. Recently, a novel family of lipids called Palmitic Acid Hydroxy Stearic Acids (PAHSAs) was discovered that are anti-inflammatory and anti-diabetic. Compelling preliminary data demonstrates that PAHSAs improve glucose homeostasis in insulin-resistant mice and this is associated with reduced intestinal inflammation and favorable shifts to gut microbial species. The central hypothesis is that the gut plays an important role in mediating the beneficial effects of PAHSAs on glucose homeostasis. The goals of this proposal are to 1) identify whether PAHSA effects on improved gut barrier function and glucose metabolism are mediated by gut T-cells, and 2) determine the contribution of the gut microbiota in mediating PAHSA effects on gut barrier function and glucose metabolism. Gnotobiotic and immunodeficient mouse models, adoptive transfer of immune and microbial cells, assessment of insulin sensitivity, and sophisticated immunology techniques will be used to determine the functional contribution of intestinal immune responses and the gut microbiota in regulating beneficial PAHSA effects on glucose metabolism. Mentorship of this innovative research proposal is led by Dr. Barbara Kahn, a leader in the field of diabetes research. Dr. Kahn will provide expertise in glucose homeostasis. Dr. Diane Mathis, a renowned immunologist and expert in T-cell immune responses, will serve as co-mentor and will provide vital expertise in immunology. Multidisciplinary expertise and guidance from Dr. Lee?s Academic Advisory Committee will provide an unparalleled environment to develop and foster Dr. Lee?s scientific and academic career goals. This K01 will extend Dr. Lee?s training experience in endocrine gut physiology and develop her expertise in gut immunology and microbiology in the context of metabolic disease. The strong mentorship team, structured training plan, and innovative research proposal will successfully foster Dr. Lee?s long-term career goal of developing an independent research program in diabetes and metabolism. This research proposal will define the mechanisms by which PAHSAs improve gut mucosal homeostasis which will identify novel therapeutic strategies to treat obesity and T2D.